- The role of erbB2 in biliary tract and esophageal carcinomas
- Biliary tract cancer : This research is focused on the role of erbB receptor tyrosine kinases during the development of biliary tract cancer (BTC) and preclinical identification of therapeutic drugs. In the United States, about 7500 new cases of BTC are diagnosed per year, and about 5000 of those cases are diagnosed as gallbladder cancer. Gallbladder carcinoma is an aggressive and frequently lethal cancer. Unfortunately, poor detection methods and screening have resulted in sustained high mortality rates. 20-50% of gallbladder carcinomas are reported to overexpress erbB2. Our laboratory generated a novel mouse model for human BTC, in which rat erbB2 is overexpressed in the basal layer of multiple epithelia, including the biliary tract epithelium, under the control of the bovine keratin 5 (BK5) promoter. Adenocarcinoma develop rapidly in the gallbladder and cystic duct of these transgenic mice at an incidence of ~90% by two months of age. The gallbladder carcinoma that develop in the BK5.erbB2 mice are sufficiently similar to human gallbladder carcinoma that develop via the adenoma-carcinoma sequence to support the relevance of this animal model as a
tool for studying BTC development and its treatment. We have found that a
number of critical signaling pathways involved in cell proliferation and survival are altered in the gallbladder of the BK5.erbB2 transgenic mice. In addition to the activation of the erbB2/EGFR and COX-2 pathways, increases in phosphorylation of Akt, MAPK and mTOR are observed in the gallbladder of transgenic mice.
Notably, during our recent studies we have shown that tyrosine kinase inhibitors (TKIs) including Gefitinib and GW2974, COX-2 inhibitors, mTOR inhibitor, rapamycin, and a novel histone deacetylase inhibitor, PCI-24781 all have significant therapeutic efficacy in the treatment of BTC in this model.
- Esophageal carcinoma: Also using the BK5.erbB2 model, our laboratory has investigated the interaction between erbB2 and bile acids to
determine their role in the etiology of esophageal cancers. It is generally recognized that gastroesophageal reflux disease and Barrett's esophagus (BE) are the major risk
factors for the development of esophageal adenocarcinoma (EAC). It is also possible that these conditions lead to the development of esophageal squamous cell carcinomas (ESCC) as well. Although it has been reported that erbB2 is strongly expressed in BE, EAC, and ESCC, the role of erbB2 in the development and progression of esophageal cancer is still unknown. We have recently found that esophageal and forestomach SCC were developed in BK5.erbB2 mice after only 4 weeks of treatment with bile only or combination of N-nitrosomethylbenzylamine (NMBA) and bile. These results suggest that bile acids may act to promote gallbladder tumorigenesis when erbB2 expression and activation are elevated. In addition, we investigated the potential therapeutic effects of PCI-24781 on NMBA- and bile-induced tumors, since HDAC inhibitors have been shown to downregulate expression of erbB2. Treatment with HDAC inhibitor resulted in a significant reduction of bile only- or NMBA/bile-induced pathogenesis in forestomach. Our results demonstrate the utility of the BKS.erbB2 mouse as a novel model for human stomach and esophageal cancers.
The role of Stat3 and Akt signalings in epithelial carcinogenesis and cell proliferation
Long-term collaboration with Dr. John DiGiovanni (DPRI) have led to the generation of valuable transgenic animal model for the studies the role of STAT3 and Akt in the skin carcinogenesis and in keratinocyte stem cell survival and proliferation. In addition, our research is focused on the role of Stat3 in the development
of psoriatic skin.
Psoriasis is the most common autoimmune disease of the human skin, affecting approximately 2% of the population worldwide. Patients with psoriasis typically have sharply demarcated chronic erythematous plaques covered by silvery white scales, which most commonly appear on the elbows, knees, scalp, umbilicus, and lumber area. Psoriasis can be a highly disabling disease that may impact a patient’s quality of life significantly. It is a chronic inflammatory disease characterized by the local activation of conventional dendritic cells (cDCs) and autoimmune T cells that trigger the abnormal proliferation and differentiation of keratinocytes in genetically susceptible individuals.
Our previous study has shown that Stat3 was activated in keratinocytes in the majority of human psoriatic lesions examined and that constitutive activation of Stat3 in keratinocytes leads to development of skin lesions that recapitulate human psoriasis both clinically and histologically in the transgenic mice, in which Stat3 is constitutively active in keratinocytes (K5.Stat3C mice). It has been suggest that activation of plasmacytoid DCs (PDCs) to produce IFN-a in the skin represents a key innate immune pathway to initiate the autoimmune T cell cascade leading to psoriasis. Currently, our research is focusing on investigating the role of PDCs during the development of
psoriasis and the effect of Stat3 activation on the distribution of PDCs.